BREAKING NEWS! Israeli Study Discovers Cross-Reactivity And Sequence Similarity Between The SARS-CoV-2 Viral Proteins And Human Gut Tissue Antigens!

Molecular Mimicry And Cross-Reactivity Shed Light on the Link Between SARS-CoV-2 And Gut Autoimmunity

COVID-19 News: Coronavirus disease 2019 (COVID-19) has been a global health concern for the past three years, causing significant morbidity and mortality worldwide. While the respiratory system has been the primary focus of SARS-CoV-2 infection, recent research highlights the virus's significant impact on the gastrointestinal tract (GIT). This raises concerns about its potential role in gut-associated autoimmune diseases. Understanding the molecular mimicry between viral antigens and human gut epitopes can provide crucial insights into the development of autoimmune conditions. In a recent study conducted by the Zabludowicz Research Center for Autoimmune Diseases-Israel, Ariel University-Israel, and Immunosciences Lab., Inc.,-USA, the sequence similarity and cross-reactivity between SARS-CoV-2 and gut antigens were explored, revealing a potential link between viral infection and gut autoimmunity.


Schematic presentation of sequence similarity that leads to cross-reactivity between SARS-CoV-2 and gut-associated ADs. (A) Sequence similarity between a SARS-CoV-2 epitope and a Human epitope. (B) Interaction of viral antigens with immune cells and activating an adaptive immune system. (C) Cross-reactivity at B cell level when clonal antibodies bind to viral epitopes and to similar self-epitopes. (D) Cross-reactivity at the T cell level involves the recognition of viral epitopes and similar self-epitopes by the same CD4 T cell. CD4 T cells initiate an immune response against SARS-CoV-2 when APC present viral epitopes on HLA-II, but the same T cells have autoreactive potential when these epitopes are similar to self-epitopes, and an immune response will be directed against host-antigens as well. (E) Autoreactive CD8 T cells that recognize viral antigens through MHC-I may directly cause tissue damage when these epitopes are similar to self-epitopes.
 
Unveiling Sequence Similarity
To investigate the sequence similarity between viral antigens and human enteric sequences, the study team employed a similarity search using experimental SARS-CoV-2 epitopes obtained from the Immune Epitope Database (IEDB) and enteric antigens from the UniProt Knowledgebase. A pairwise local alignment tool, EMBOSS Matcher, was utilized to identify matching sequences. The study identified sequence similarities and targeted cross-reactivity between 10 pairs of immunoreactive epitopes. Notably, these similarities were found in viral proteins related to ulcerative colitis, primary biliary cholangitis, celiac disease, and autoimmune hepatitis, aligning with seven enteric antigens implicated in these gut-associated autoimmune conditions.
 
Implications of Cross-Reactivity
The antibodies produced against viral proteins that cross-react with human gut antigens play crucial roles in various cellular functions. The study highlights the potential contribution of these intestinal cross-reactive epitopes to SARS-CoV-2 infection and their potential role in the development of gut autoimmunity.

Understanding the relationship between these cross-reactive antibodies and the associated autoimmune diseases opens new avenues for research into the pathogenesis and treatment of these conditions.
 
COVID-19 and Autoimmune Diseases
COVID-19 has been linked to a wide range of autoimmune diseases, and the SARS-CoV-2 virus itself is now recognized as an auto-immunogenic virus. Autoimmune diseases have been identified as part of the long COVID syndrome as reported in various studies and past COVID-19 News reports, leading to concerns about a potential increase in their incidence. While genetic factors are known to contribute to autoimmune diseases, environmental factors, including viral infections, can play a significant role in their development. The study emphasizes the importance of investigating the molecular mimicry between SARS-CoV-2 and gut epitopes in understanding the potential autoimmune consequences of the virus.
 
The Gut-Immune System Connection
The human gastrointestinal tract is susceptible to various environmental factors that can trigger autoimmune responses. Factors such as increased gut permeability, dysbiosis, and horizontal gene transfer can lead to systemic autoimmunity. Molecular mimicry, epitope spreading, and immune cross-reactivity between non-self- and self-antigens have been proposed as mechanisms driving SARS-CoV-2-associated autoimmunity. However, the specific molecular mimicry between the virus and intestinal epitopes has been under-investigated. This study fills that gap and sheds light on the sequence similarity and cross-reactivity between SARS-CoV-2 and gut-associated autoimmune diseases.
 
Unraveling the Pathways
The study not only identifies the shared sequences and cross-reactivity but also examines the potential pathological involvement of the human proteins in the development of autoimmune diseases. The shared sequences were found to be involved in essential cellular functions related to celiac disease (CD), autoimmune hepatitis (AIH and other gut autoimmune diseases……including cell division, tight junction integrity, muscle contractility, immune modulation, and epigenetic modification. The study highlights the significance of these proteins in the gut immune response and their potential dysregulation during SARS-CoV-2 infection.
 
The Clinical Implications
The cross-reactivity between SARS-CoV-2 proteins and human tissue antigens, especially in the gut and liver, has important clinical implications. It suggests that the immune response triggered by viral infection or vaccination can result in the production of cross-reactive antibodies that target self-antigens. This autoimmune cascade can contribute to the development of gut-associated autoimmune diseases, and potentially, extra-intestinal manifestations of COVID-19. Understanding these mechanisms is crucial for the safe development and administration of anti-COVID-19 vaccines, to minimize the risk of inducing or exacerbating autoimmune diseases.
 
Looking Ahead
While this study provides groundbreaking insights into the molecular mimicry between SARS-CoV-2 and gut-associated autoimmune diseases, further research is needed. Future investigations should explore the specific cross-reactive epitopes and their implications for autoimmunity. Moreover, with the emergence of new SARS-CoV-2 variants, it is essential to understand how these variations might affect sequence similarity and cross-reactivity with gut antigens. A comprehensive understanding of the interplay between viruses and autoimmune diseases can aid in the development of effective therapeutic strategies and improve public health outcomes.
 
Conclusion
The study findings shed light on the molecular mimicry and cross-reactivity between SARS-CoV-2 and gut-associated autoimmune diseases. The identified sequence similarities and cross-reactive epitopes provide important insights into the mechanisms underlying the development of gut autoimmunity. This research contributes to our understanding of the complex interplay between viral infections and autoimmune diseases, with implications for the diagnosis, treatment, and prevention of these conditions. Further investigations are required to elucidate the specific epitopes involved and to assess the implications for vaccine development and administration.
 
The study findings were published in the peer reviewed journal: Biomedicines.
https://www.mdpi.com/2227-9059/11/7/1937
 
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